EXCEED THE SPACE PROVIDED. It is proposed to establish a COBRE comprised of 5 research projects headed by junior and early career faculty and 3 research core facilities. The scientific theme of the Center will be cancer signaling networks, namely, the molecular mechanisms by which signaling networks relevant to carcinogenesis are regulated: transcription, protein phosphorylation and protein degradation. Some of the focal points of the proposed research will be DNA repair, Wnt and IGF-1 signaling, proteome-wide analysis of protein phosphorylation, ubiquitin-mediated proteolysis, global RNA polymerase II machinery, transgenic mouse models of carcinogenesis, and bioinformatic inference of network systems. Cancers under investigation will include hepatocellular carcinoma and ovarian follicular cancer. Two of the investigators will continue from the current COBRE (Drs. Singer, Zhitkovich), and 3 are newly hired junior faculty. The proposed research core are Mouse Transgenics, Genomics, and Bioinformatics. The first two carry over from the current Center, while the latter will be established as a new core facility. Each project leader and core director has an assigned senior faculty mentor. The mentors comprise the IAC which is chaired by the PI. The EAC evaluates all aspects of the Center's operation and advises the PI and the IAC. The PI is also advised by the Steering Committee of the Brown Center for Genomics and Proteomics, and reports to the Dean of the Medical School and the senior administration. The of the program is to establish both a thematic focus and the caliber of science required for a transition to a PPG funded by the NCI. The following Specific Aims are proposed to achieve these goals: Aim 1: To investigate the role of the gonad-specific transcriptional coactivator TAF4b in the development of ovarian granulosa cell cancer; Aim 2: To examine the function of Wnt signaling networks in the development of hepatocellular carcinoma and to address whether targets in this pathway may be useful for cancer therapy; Aim 3: To describe and functionally test, on a proteome- wide basis, cascades of tyrosine protein phosphorylationtriggered by receptor crosslinking in mast cells and by IGF-1stimulation in hepatocellular carcinoma cells; Aim 4: To elucidate the mechanisms by which Cullin 3 complexes recognize regulatory proteins causally connected to cell cycle aberrations found in cancer and target them for ubiquitin-mediatedproteolysis; Aim 5: To discover novel mechanisms by which normal levels of oxidative stress found in all cells participate in generating DNA damage that ultimately leads to the development of cancer. '